(a) Field of the Invention
The present invention relates to derivatives of 5-carbamoyl-adamantan-2-yl amide, pharmaceutically acceptable salts thereof, and uses of the 5-carbamoyl-adamantan-2-yl amide derivatives and/or pharmaceutically acceptable salts thereof for inhibiting the activity of 11β-hydroxysteroid dehydrogenase type 1 (11b-HSD1) and/or for preventing and/or treating of various diseases mediated by 11β-hydroxysteroid dehydrogenase type 1.
(b) Description of the Related Art
Glucocorticoid (cortisol in humans, corticosterone in mice and rats), a type of adrenocorticosteroid, plays critical roles of regulating a range of metabolism and homeostasis, getting involved in a stress-related reaction, and the like. Such actions of glucocorticoid are performed via bonding the active glucocorticoid with a glucocorticoid receptor (GR). Interconversion between the active 11-hydroxy glucocorticoid (cortisol in humans) and the inactive 11-keto glucocorticoid (cortisone in humans) is catalyzed by the endoenzyme, 11β-hydroxysteroid dehydrogenase (11b-HSD), which is present in two isoforms. 11β-hydroxysteroid dehydrogenase type 1 (11b-HSD1) takes a part in turning an inactive 11-keto metabolite into an active 11-hydroxy metabolite, while 11β-hydroxysteroid dehydrogenase type 2 plays a role of switching the active form to the inactive form. The active 11-hydroxy glucocorticoid engages in regulating phosphoenolpyruvate carboxykinase (PEPCK), which is a major enzyme for gluconeogenesis through the bonding with the intracellular glucocorticoid receptor.
Gluconeogenesis is a process of glucose synthesis process that takes place in the liver, and it involves the actions of major enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) promoting the conversion of oxaloacetate into phosphoenolpyruvate and glucose-6-phosphatase (G6Pase) facilitating hydrolysis of glucose-6-phophate to provide free glucose. In this regard, the rate-controlling step determining the rate of gluconeogenesis is the conversion of oxaloacetate into phosphoenolpyruvate, which is promoted by the phosphoenolpyruvate carboxykinase.
In particular, fasting brings about up-regulation of both phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, resulting in an increased rate of gluconeogenesis and thereby the blood glucose level is also getting higher. Accordingly, inhibiting the activity of 11β-hydroxysteroid dehydrogenase type 1 (11b-HSD1) may regulate the concentration of the active 11-hydroxy glucocorticoid, control phosphoenolpyruvate carboxykinase, and decrease the blood glucose level, and thereby it can be a useful approach for treating diabetes.
Besides the foregoing biochemical reviews, some small-scale clinical researches for humans or transformed mice have evidenced the potential for treating diabetes via the inhibition of 11β-hydroxysteroid dehydrogenase type 1.
An experiment conducted with using transformed mice has revealed that modulating the activity of 11β-hydroxysteroid dehydrogenase type 1 may bring forth beneficial effects of treating diabetes and metabolic syndrome. For example, in case of knockout mice lacking a gene of 11β-hydroxysteroid dehydrogenase type 1, fasting led to no increase in the amount of phosphoenolpyruvate carboxykinase and glucose-6-phophatase and they did not develop hyperglycemia associated with stress or obesity, as well (See, Kotolevtsev Y. et al., Proc. Natl. Acad. Sci. USA 1997, 94, 14924). In addition, the knockout mice lacking a gene of 11β-hydroxysteroid dehydrogenase type 1 showed an improvement on a lipid profile and insulin sensitivity and was found to have a glucose tolerance function (See, Morton et al., J. Biol. Chem. 2001, 276, 41293). A research was further conducted regarding mice with the over-expressed gene of 11β-hydroxysteroid dehydrogenase type 1. The mouse with the over-expressed gene of 11β-hydroxysteroid dehydrogenase type 1 showed an increased concentration of corticosterone and an enhanced activity of 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue. It also induces phenotypes of abdominal obesity and syndrome-X. In particular, when being fed on a high fat diet, the mouse showed a considerably increased level of obesity, and it also had a high level of blood glucose and insulin even when being fed on a low fat diet. Moreover, they exhibited impaired glucose tolerance and insulin resistance (See, Masuzaki et al., Science 2001, 294, 2166).
In addition, a small-scale clinical trial for carbenoxolone, a non-selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1, confirmed that 11β-hydroxysteroid dehydrogenase type 1 may have an effect of treating diabetes. There was a research discovering that carbenoxolone increases systemic insulin sensitivity through a decrease in a liver glucose production (See, Walker Et al., J. Clin. Endocrinol. Metab. 1995, 80, 3155). In another research, diabetic patients being administered with carbenoxolone were found to have a decreased level of glucose production even when they were administered with glucagon, and they also showed a decreased level of glycogen decomposition. However, such phenomenon was not observed in a healthy person, though (See, Andrews et al. J. Clin. Endocrinol. Metab. 2003, 22, 285). Such results indicated that regulating the activity of 11β-hydroxysteroid dehydrogenase type 1 may have an effect of treating diabetes and metabolic syndrome.
Besides, recent research has showed that the inhibition of 11β-hydroxysteroid dehydrogenase type 1 enables amelioration of hypertension (See, Masuzaki et al., J. Clin. Invest. 2003, 12, 83; Rauz et al., QJM 2003, 96, 481).
With taking all these reports into account, one may draw a conclusion that the inhibition of 11β-hydroxysteroid dehydrogenase type 1 will be able to present safe and effective approaches for treating symptoms of various diseases such as diabetes, metabolic syndrome, and the like.